The acute articular inflammation of gouty arthritis is caused by crystallisation of sodium urate in an articulation. Interaction between monosodium urate crystals (MSU crystals) and monocytes, platelets, synoviocytes, macrophages and neutrophils within the articulation initiates an inflammatory response by stimulating the secretion of proinflammatory agents and chemotactic factors from these different cell types. Some of these mediators induce the accumulation of neutrophils, which further enhances the inflammatory response and release of oxygen radicals and proteolytic enzymes, leading to the destruction of the articulations.
Arthritis is a chronic syndrome characterized by the inflammation of peripheral joints, while gout manifests itself as an inflammation of the lower leg. Although the causal agents differ between the two diseases, the mechanism of migration of neutrophils is similar in both diseases. Therefore, for the sake of brevity, whenever reference hereinbelow is made to arthritis, it should be understood as encompassing gout, since both diseases are similar. There is a wide spectrum of disease severity and many patients run a course of intermittent relapses and remissions with an overall pattern of slowly progressive joint destruction and deformity. Persistent inflammation produces symptoms and damages tissue causing loss of cartilage, erosion of bone matter and subluxation of the joint. This results in a high degree of morbidity resulting in disturbed daily life of the patient. Diagnosis of arthritis is typically carried out by determination of rheumatoid factors in the blood and radiological changes in peripheral joints.
Transendothelial migration of neutrophils is a critical stage in the development of the inflammatory reaction. To infiltrate an articulation, the neutrophils must migrate from the blood through the endothelium and the synovial tissue. This migration occurs through a multistep process.
First, interactions between integrins, selectins and glycans mediate neutrophil rolling along the endothelium. Neutrophils are then activated, leading to changes in β2 integrin to an active conformation. This change of conformation is thought to be induced by chemotactic factors expressed by endothelial cells such as platelet activating factor (PAF) or interleukin-8 (IL-8). Activation of integrins causes neutrophils to adhere strongly to the endothelium, allowing them to extravasate. Once in the tissue, neutrophils follow concentration gradients of chemoattractants such as complement peptide C5a, leukotriene B4 (LTB4) and IL-8.
Factors involved in neutrophil migration in gout pathogenesis remain largely unknown. For example, while LTB4 is known to be produced by MSU crystal-activated neutrophils, inhibition of LTB4 synthesis does not reduce MSU crystal-induced neutrophil recruitment in the subcutaneous air pouch model in rats. However, inhibition of PAF partially diminishes MSU crystal-induced arthritis in rabbits articulations. It has been observed that IL-8 can be the major cystein-x-cystein (C—X—C) chemokine involved in neutrophil migration in response to MSU crystals. Inactivation of IL-8 with specific blocking antibodies seems to lead to a reduction of neutrophil migration in rabbit articulations.
However, this reduction was observed 12 hours after MSU crystals injection, with no effect detected at earlier time points. This strongly suggests that IL-8 is not responsible for the initiation of the inflammatory response induced by MSU crystals. However, early neutrophil migration in response to MSU crystals is impaired in mice deficient in the murine IL-8 receptor homologue CXCR2. Since CXCR2 does not solely bind IL-8, this suggest that other chemokines or inflammatory mediators could be involved at the beginning or even during the inflammatory response.
Primary treatments of arthritis include first line drugs for control of pain and inflammation classified as non-steroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin, ibuprofen, naproxen, methotrexate, etc. Secondary treatments include corticosteroids, slow acting antirheumatic drugs (SAARDs) or disease modifying drugs (DMs), e.g., pencillinamine, cyclophosphamide, gold salts, azothipprine, levamisole, etc.
All of the above-mentioned products have a variety of toxic side effects and most of them are cytotoxic. These drugs have limited advantages and their effects are mainly of short term duration. The side effects they produce, e.g., gastric erosion, and adverse effects on the kidneys and liver, dictate against their use over extended periods of time. Further the products primarily used are costly and have low benefit-risk ratios.
There still remains a need for alternative therapies, methods, and compositions or compounds for the modulation of inflammatory reactions which are moderate in cost, safe, efficient and which eliminate the need for traditional products and their associated side effects, particularly over prolonged daily use.